The serotonin system governs many higher order neural functions that control the interaction and perception of an individual with their internal and external environment. As such, dysfunction of the serotonin system has been implicated in a wide variety of psychopathologies. Deficits in serotonin appear to precipitate depression and anxiety disorders more frequently in women, but deficits in serotonin in men often underlie irritability, hostility, anger, rage, and aggression leading to violence. Psychologically this has been attributed to women turning anger inward, versus men turning anger outward due to social rearing experience. This notion is unsatisfying on a molecular level and it does not integrate knowledge of androgens and aggression in animals. Since the serotonin system mediates impulsive behavior and aggression, it has been reasoned that androgens act on the serotonin system to reduce serotonin and thereby increase impulsivity. However, knowledge of the steroid receptor profile in serotonin neurons of male human and nonhuman primates is lacking and little is known of the actions of androgens on gene expression in serotonin neurons. We hypothesize that serotonin neurons in male primates express estrogen receptor beta (ER) and androgen receptors (AR) and that the balance of activity at these receptors governs serotonin synthesis and neural function, which in turn, controls aggression. To test this hypothesis, 5 aims are proposed. Aims 1 and 2 will establish groups of male macaques and manipulate the activity of ER2 and AR with enzyme inhibitors and a selective ER agonist, 8BV-E from Bayer-Schering. Behavior and global serotonin will be assessed. Aims 3, 4 and 5 will determine whether ER, AR, and pivotal metabolic enzymes are localized in serotonin neurons and whether they are regulated by testosterone metabolites. In addition, the regulation of serotonin-related genes TPH2, SERT, 5HT1A, MAO-A and MAO-B will be determined with in situ hybridization. Serotonin fiber density will be measured in the locus coeruleus with immunocytochemistry and stereology for an indication of serotonin neurotransmission, and to obtain preliminary support for the potential involvement of norepinephrine. Together, these experiments will further our understanding of the regulation of the serotonin system in male primates. PUBLIC HEALTH RELEVANCE: Androgens increase aggression and violent, impulsive behavior and the serotonin system regulates these behaviors. The goal of this grant is to determine how androgens regulate the serotonin neural system in male nonhuman primates. A regulatory mechanism is proposed that could lead to a novel treatment in psychiatric illnesses with explosive rage and impulse disorders.